Lordick F, Mauer M E, Stocker G, Cella C A, Ben-Aharon I, Piessen G, Wyrwicz L, Al-Haidari G, Fleitas-Kanonnikoff T, Boige V, Lordick Obermannová R, Martens U M, Gomez-Martin C, Thuss-Patience P, Arrazubi V, Avallone A, Shiu K K, Artru P, Brenner B, Buges Sanchez C, Chau I, Lorenzen S, Daum S, Sinn M, Merelli B, van Grieken N C T, Nilsson M, Collienne M, Giraut A, Smyth E
Department of Medicine (Oncology, Gastroenterology, Hepatology, Pulmonology), University of Leipzig Medical Center, Comprehensive Cancer Center Central Germany (CCCG), Leipzig, Germany.
European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium.
Ann Oncol. 2025 Feb;36(2):197-207. doi: 10.1016/j.annonc.2024.10.829. Epub 2024 Nov 13.
Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection.
VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.
The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations.
Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.
接受新辅助化疗和切除术后，伴有肿瘤阳性淋巴结（ypN+）或手术切缘阳性（R1）的胃食管腺癌患者复发风险很高。辅助性纳武单抗对食管/食管胃交界癌以及放化疗和手术后的残留病理疾病有效。免疫检查点抑制在晚期胃食管癌中已显示出疗效。我们假设，对于新辅助化疗和切除术后的高危（ypN+和/或R1）胃食管腺癌患者，纳武单抗/伊匹单抗比辅助化疗更有效。
VESTIGE是一项国际性学术多中心开放标签随机II期试验，评估辅助性纳武单抗/伊匹单抗与化疗在复发风险高的胃食管腺癌中的疗效。患者按1:1随机分组，接受标准辅助化疗（与新辅助化疗方案相同）或纳武单抗3mg/kg静脉注射，每2周一次，加伊匹单抗1mg/kg静脉注射，每6周一次，共1年。关键纳入标准包括新辅助化疗加手术后的ypN+和/或R1状态。主要终点是意向性治疗人群的无病生存期。次要终点包括总生存期、局部和远处失败率，以及根据美国国立癌症研究所不良事件通用术语标准第5.0版评估的安全性。
独立数据监测委员会于2022年6月审查了计划入组的240例患者中的189例的数据，并因无效而建议停止招募。在最终分析时，195例患者（98例接受纳武单抗/伊匹单抗治疗，97例接受化疗）的中位随访时间为25.3个月。纳武单抗/伊匹单抗组的中位无病生存期为11.4个月[95%置信区间（CI）8.4 - 16.8个月]，而化疗组为20.8个月（95%CI 15.0 - 29.9个月），风险比为1.55（95%CI 1.07 - 2.25，单侧P = 0.99）。12个月无病生存率分别为47.1%和64.0%。不存在毒性问题或过多的早期停药情况。
对于新辅助化疗和手术后伴有ypN+和/或R1的胃食管腺癌患者，与化疗相比，纳武单抗/伊匹单抗并未改善无病生存期。
